Regional Distribution of the Anticonvulsant and Behavioural Effects of Muscimol Injected into the Substantia Nigra of Rats

Abstract

Previous anatomical investigations have reported a direct projection from substantia nigra pars lateralis to the dorsal midbrain anticonvulsant zone. The present study tested the hypothesis that the anticonvulsant properties of nigral inhibition previously attributed to substantia nigra pars reticulata were, in fact, due to the suppression of neural activity in the adjacent pars lateralis. Using the electroshock model of epilepsy, a systematic map of the anticonvulsant effects of bilateral injections of muscimol (60 ng/0.5 mu l per side) into different parts of substantia nigra was constructed. Electroshock (1 s of 40 mA 50 Hz AC) was administered via ear-clip electrodes 5 or 60 min following injections of muscimol, or 60 min after control injections of saline. To provide insight into the functional mechanisms whereby nigral inhibition might suppress tonic seizures the behavioural effects elicited by muscimol were also noted. No evidence supporting the experimental prediction was found. The most sensitive region of substantia nigra for suppressing tonic hindlimb extension was caudal pars reticulata. These data indicate a serious mismatch between the results of microinjection mapping studies and underlying patterns of anatomical connectivity. The behavioural reaction most closely associated with tonic seizure suppression was stereotyped locomotion; both were obtained maximally from caudal pars reticulata. Rostral substantia nigra was associated more with oral stereotypy, while a raised head position was observed at lateral injection sites and a lowered positioning of the head at medial locations. These data suggest that the rat substantia nigra may contain a functional organization based on a form of somatomotor topography. This organization may influence which part of the substantia nigra is most effective in suppressing seizures expressed by different muscle groups of the body.

Regional neural activity within the substantia nigra during peri-ictal flurothyl generalized seizure stages

“…The findings confirm previous local injection, histological, and receptor subtype studies suggesting that the two regions are different (Fan et al, 1997;Galanopoulou et al, 2003;Hedberg et al, 2003;Moshéet al, 1994;Ravizza et al, 2003;Shehab et al, 1996;Thompson et al, 2000;Velíšek et al, 2005;Velíšková et al, 1998) and provide new information regarding the SNR projection targets and other basal ganglia activity during the pre-clonic/tonic-clonic and postictal period. Importantly, the differentiation between two subregions within the SNR was detected without any lesion or local drug infusion (Garant and Gale, 1983;Moshé et al, 1994;Shehab et al, 1996;Velíšková and Moshé, 2001). The observation that the early-stage flurothyl-induced seizure events use these regions and their pathways identifies them as possible experimental and clinical interventions.…”

“…However, investigators also found that there are two anatomically discrete regions in the SNR of adult rats, the SNR anterior and the SNR posterior (Fan et al, 1997;Moshé et al, 1994;Shehab et al, 1996;Thompson et al, 2000;Velíšková and Moshé, 2001). These two regions mediate separate facilitatory or inhibitory effects on seizures in response to localized microinfusions of agents that modulate GABA A receptor neurotransmission (Moshé et al, 1994;Thompson et al, 2000;Velíšková and Moshé, 2001;Velíšková et al, 1996), and glutamatergic or dopaminergic systems (Fan et al, 1997;.…”

Local distribution and toxicity of prolonged hippocampal infusion of muscimol

“…20 In rodents, seizure frequency has been suppressed with bilateral infusions of 0.01 µg (88 pmol) 18 in the mouse and 0.06 µg in the rat. 41 Muscimol is rapidly cleared from the blood of rats following intravenous administration of 8 µmol/kg. 3 After intracerebroventricular injection of 0.8 nmol (5.3 nmol/kg) muscimol, recovery in the brain was 55% at 30 minutes.…”

“…6,14,19,28,40,41,44 Results of animal studies have identified neuronal populations, receptors, and ion channels that are most important in seizure onset and propagation. Infusion of ibotenic acid, an excitatory amino acid, which selectively affects the N-methyl-D-aspartate-receptor, extinguishes epileptiform activity in a rat model of temporal lobe epilepsy, presumably by eliminating a hyperexcitable focus of neurons.…”

Modulation of synaptic GABAAreceptor function by zolpidem in substantia nigra pars reticulata

“…However, a recent study revealed that the GABA A receptor mediated inhibitory PSC, and α subunit expression were not reduced in the SNr of gerbils with inherited epilepsy [33] . Functional studies have shown that a microinjection of muscimol into the SNr suppressed the electroshock model of epilepsy [34] , while bicuculline infusions are proconvulsant [35] . The intranigral transplantation of GABA-producing cells have been shown to exhibit significant anticonvulsant effects in experimental epilepsy [36] .…”